This chapter discusses different aspects related to the operation of natural gas systems in the framework of the new configuration of energy systems based on the smart grid concept. First of all, different experiences performed worldwide regarding the application of demand response principles to increase the efficiency and operability of natural gas networks are presented. Next, the characteristics of the natural gas system to be configured according to the smart grid architecture are discussed, including the necessary agents for the proper functioning of such infrastructure. After that, the current state of installation of gas smart meters in some European countries is presented, according to the massive rollout process promoted by the European Union. Barriers that prevent the full exploitation of demand response resources related to natural gas systems are presented in the next section. After that, technical constraints which may be solved by using demand response are presented. Finally, last tendencies related to the development of natural gas systems, such as the injection of hydrogen, are considered